To Operate or Not to Operate? Reconstructive Surgical Burden and Quality of Life of Pediatric Patients with Facial Differences.

OBJECTIVE: The Craniofacial Condition Quality of Life Scale (CFC-QoL) was used to evaluate the relationship between surgical burden and quality of life (QoL). DESIGN: Patient-parent dyads completed the CFC-QoL which queries the following QoL domains: Bullying, Peer Problems, Psychological Impact, Family Support, Appearance Satisfaction, and Desire for Appearance Change. Stepwise multivariate linear regressions were performed for each QoL domain. SETTING: Urban tertiary care center. PATIENTS, PARTICIPANTS: Pediatric patients with facial differences, and their parents. INTERVENTION: Survey study. MAIN OUTCOME MEASURE(S): Demographic, diagnostic, and surgical characteristics were collected. Surgical burden was calculated as the standard deviation from the mean number of surgeries per diagnostic cohort. RESULT: Patients (N = 168) were majority female (57.1%) and Hispanic (64.3%). Diagnoses were cleft lip and/or palate (CLP,n = 99) or other craniofacial conditions (CFC,n = 69). Average patient age was 2.3 ± 5.6 years at first reconstructive surgery and 12.3 ± 3.4 years at study enrollment. Patients received an average of 4.3 ± 4.1 reconstructive surgeries.Worse Bullying was associated with higher surgical burden. Worse Peer Problems was associated with higher surgical burden, but only for children with non-CLP CFCs. Worse Family Support was associated with CFC diagnosis, female sex, and higher surgical burden. Worse Psychological Impact was associated with higher surgical burden. Worse Appearance Satisfaction was associated with younger age and with lower surgical burden. Greater Desire for Appearance Change was associated with older age, higher surgical burden, CLP diagnosis, female sex, and non-Hispanic ethnicity. Socioeconomic status did not predict QoL per patient self- or parent-proxy report. CONCLUSIONS: Higher surgical burden was associated with worse QoL outcomes in multiple domains.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling. RESULTS: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders. CONCLUSIONS: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Tissue Expander-Assisted Component Separation for Pediatric Abdominal Wall Reconstruction.

BACKGROUND: Tissue expander-assisted component separation can be used to increase the amount of skin, muscle, and fascial components available for repair of congenital abdominal wall defects via a staged approach without the need for flap reconstruction. We present the largest case series to date using a tissue expander-assisted component separation technique for treatment of congenital abdominal wall defects in a pediatric patient population. METHODS: A retrospective chart review of 9 patients with large congenital abdominal wall defects not initially amenable to primary repair between 2009 and 2020 was performed. Patients first underwent placement of tissue expanders, followed by removal once they had reached a sufficient expander volume. Component separation, with and without mesh placement, was performed to achieve abdominal wall closure. RESULTS: The average age of patients at primary repair was 3.2 years (SD ±1.7 years). Eight patients (88.8%) had congenital omphalocele, and 1 patient (11.1%) had gastroschisis; none were amenable to primary repair. The average size of the defects before closure was 87.6 cm2 (SD = 33.6 cm2). Eighteen tissue expanders were placed in 9 patients, 72.2% of which were placed in the plane between the external and internal oblique muscles. Patients were seen in clinic an average of 6.8 times (SD, ±3.3 visits) for volume expansion into the tissue expander, receiving an average of 32.0 mL in each per visit. An average of 4.3 months (SD, ±1.8 months) elapsed between placement and removal of the expanders. At the time of tissue expander removal and abdominal wall closure, the defects ranged from 30 to 132 cm2 (mean, 54 cm2). All defects were successfully repaired using a component separation and bilateral fasciocutaneous flap advancement. Two patients (18.2%) experienced infection of the surgical site and seroma, both of which required debridement. One patient (9.1%) experienced partial thickness skin necrosis that was managed nonsurgically. The overall complication rate was 36.4%. CONCLUSIONS: Omphalocele and gastroschisis can produce abdominal wall defects that are not amenable to primary repair. Staged reconstruction using tissue expander-assisted component separation is a safe and effective method of obtaining adequate local soft tissue to achieve primary closure.

Reduction of Work-Related Musculoskeletal Disorders in Plastic Surgeons by Introduction of a Posture Training Device.

BACKGROUND: Plastic surgeons have an increased risk for the development of musculoskeletal disorders because of frequent poor ergonomics of the operating room. This study characterizes selected plastic surgery procedures, with an attempt to identify high-risk procedures and procedural components as well as the impact of biofeedback on surgical ergonomics. METHODS: A commercially available posture training device was used to initially record neck and spine positioning and later to send biofeedback to prompt surgeons to correct posture. Device data were correlated with in-person observations to characterize factors associated with more time spent in the slouched/nonneutral cervical and thoracic spine posture. RESULTS: The proportion of time spent in the upright position during surgery was significantly different among male and female participants, level of training, participant height, in the sitting versus nonsitting positioning (P < 0.001), with loupes use, and if there was more than an 8-inch height difference between 2 participants (mean, 0.70 ± 0.285). Using the device intervention, all participants spent a larger proportion of operating time upright. Half of these improvements in posture were statistically significant. While in feedback mode, participants experienced shorter and more frequent periods of slouching/nonneutral posture. When comparing the same participant performing the same procedure with and without device biofeedback, 72.2% of participants spent more time in the upright/neutral posture during the surgery when the device was sending feedback. CONCLUSIONS: Biofeedback devices used in the operating room can lead to improved surgical posture, which may translate to reduction of workplace injuries, and overall physician health. This study found that a commercially available posture training device and sitting stools in the operating room could significantly improve physician cervical and thoracic spine posture.

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E -/- mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0-10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.

A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma.

BACKGROUND: Effective therapies are lacking for recurrent, metastatic adenoid cystic carcinoma (R/M ACC) and preclinical models suggest retinoic acid agonists inhibit ACC growth. This phase II trial evaluated all-trans retinoic acid (ATRA) as a novel therapy for ACC. METHODS: Patients with R/M ACC (any site) with clinical and/or radiographic progression ≤12 months prior to study entry were eligible. Cohort 1 (CH1) received ATRA 45 mg/m2 split oral daily dosing on days 1-14 of a 28-day cycle; Cohort 2 (CH2) received the same dosing continuously. Primary endpoint was best overall response rate (CR + PR) (RECIST v1.1). Secondary endpoints: safety and progression-free survival (PFS). Exploratory analyses: ATRA impact on MYB expression and genomic predictors of response. RESULTS: Eighteen patients enrolled. There were no responses, but 61% (11/18) had stable disease (SD) and 28% (5/18) progression as best response; 11% (2/18) unevaluable. Median duration of stability: 3.7 months (95%CI, 1.9-3.9). One patient (CH1) remains on drug with SD approaching 1 year. Half of those who received prior VEGFR therapy achieved SD (4/8). At median follow up of 7.9 months, median PFS was 3.2 months (95%CI, 1.8-3.9). N = 1 required dose adjustment; N = 1 came off drug for toxicity. There were no grade 3-4 adverse events. NOTCH1 and PI3K pathway alterations were most frequent. Low MYB protein expression was associated with longer duration of stability on ATRA (P < 0.01). CONCLUSION(S): While the trial did not meet its prespecified response endpoint, ATRA alone or in combination may be a low toxicity treatment for disease growth stabilization in R/M ACC.

Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition.

BACKGROUND: Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart. METHODS: Diabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice. RESULTS: Mice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e':a' ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6Chi monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice. CONCLUSIONS: Murine diabetes results in distinct changes in cardiac cellularity. These changes-in particular increased levels of fibroblasts-offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.

Symptoms of Depression and Anxiety in Patients With Type 2 Diabetes in a Canadian Outpatient Cardiac Rehabilitation Program.

PURPOSE: The objective of this study was to determine whether type 2 diabetes status is associated with an increased likelihood of depressed mood and anxiety in patients attending cardiac rehabilitation (CR) and to explore predictors of depression and anxiety after CR completion in patients with diabetes. METHODS: A retrospective analysis was conducted in patients who completed a 12-wk CR program between 2002 and 2016. Patients were classified as reporting normal-to-mild or moderate-to-severe symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS). Logistic regression models were used to compare predictors of depression and anxiety prior to CR enrollment and investigate predictors of post-CR HADS scores among a subset of patients with diabetes. RESULTS: Data from 6746 patients (mean age 61 ± 11 yr, 18% female, 18% with diabetes) were analyzed. After controlling for known predictors of depression, patients with diabetes were not more likely to report moderate-to-severe levels of depression prior to or after completing CR. In patients with diabetes, younger age predicted moderate-to-severe depression post-CR (OR = 0.95: 95% CI, 0.93-0.98). Patients with diabetes were also more likely to report moderate-to-severe levels of anxiety after completing CR (OR = 1.45: 95% CI, 1.02-2.07). Younger age (OR = 0.93: 95% CI, 0.88-0.97) and smoking status (OR = 3.3: 95% CI, 1.15-7.06) predicted moderate-to-severe post-CR anxiety in patients with diabetes. CONCLUSIONS: Patients with diabetes, particularly younger patients who currently smoke or recently quit, are more likely to report having anxiety following CR. These patients may therefore require additional management of anxiety symptoms during CR. Larger studies of CR patients with diabetes and more variable depression and anxiety levels are needed.

Orbital Volumetric Analysis in Patients With Unicoronal Craniosynostosis: A Comparison Between Distraction Osteogenesis and Fronto-Orbital Advancement.

BACKGROUND: Unicoronal craniosynostosis is associated with orbital restriction and asymmetry. Surgical treatment aims to both correct the aesthetic deformity and prevent the development of ocular dysfunction. We used orbital quadrant and hemispheric volumetric analysis to assess orbital restriction and compare the effectiveness of distraction osteogenesis with anterior rotational cranial flap (DO) and bilateral fronto-orbital advancement and cranial vault remodeling (FOAR) with respect to the correction of orbital restriction in patients with unicoronal craniosynostosis. METHODS: A retrospective review of all patients with a diagnosis of unicoronal craniosynostosis and treated with either DO or FOAR from 2000 to 2019 was performed. Preoperative and postoperative total orbital volumes, as well as quadrant and hemispheric volume ratios, were calculated from 3-dimensional head computed tomography scans. Selected preoperative and postoperative orbital measurements, including the maxillary length of the orbit (MLO; zygomaticofrontal suture to the top of zygomatic arch) and the sphenoid length of the orbit (SLO; the top of sphenoid suture to the top of zygomatic arch), were also obtained. RESULTS: Data were available for 28 patients with unicoronal craniosynostosis. Mean preoperative total orbital volume was significantly smaller on the synostotic side compared with the nonsynostotic side (10.94 vs 12.20 cm3, P = 0.04). Preoperative MLO and SLO were significantly longer on the synostotic side compared with the nonsynostotic side (MLO: 20.26 vs 17.75 mm, P < 0.001; SLO: 26.91 vs 24.93 mm, P = 0.01). Distraction osteogenesis and FOAR produced significantly different changes in orbital quadrant and/or hemispheric volume ratios on the nonsynostotic side but not on the synostotic side. CONCLUSIONS: Before correction, patients with unicoronal craniosynostosis have significantly smaller total orbital volumes on the synostotic side compared with the nonsynostotic side and significantly greater MLO and SLO on the synostotic side compared with the nonsynostotic side. There is no significant difference between DO and FOAR with regard to correcting the observed orbital restriction in these patients.

Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes.

OBJECTIVE: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-xL (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-xPlt20) or wild-type littermate controls into atherosclerotic-prone Ldlr+/- mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-xL function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-xPlt20 bone marrow transplanted Ldlr+/- mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-xL with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe-/- mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. CONCLUSIONS: These studies suggest that selectively reducing circulating platelets, by targeting Bcl-xL to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.

Social Isolation and Psychological Distress Among Older Adults Related to COVID-19: A Narrative Review of Remotely-Delivered Interventions and Recommendations.

The COVID-19 pandemic is associated with several short- and long-term negative impacts on the well-being of older adults. Physical distancing recommendations to reduce transmission of the SARS-CoV2-19 virus increase the risk of social isolation and loneliness, which are associated with negative outcomes including anxiety, depression, cognitive decline, and mortality. Taken together, social isolation and additional psychological impacts of the pandemic (e.g., worry, grief) underscore the importance of intervention efforts to older adults. This narrative review draws upon a wide range of evidence to provide a comprehensive overview of appropriate remotely-delivered interventions for older adults that target loneliness and psychological symptoms. These include interventions delivered by a range of individuals (i.e., community members to mental health professionals), and interventions that vary by implementation (e.g., self-guided therapy, remotely-delivered interventions via telephone or video call). Recommendations to overcome barriers to implementation and delivery are provided, with consideration given to the different living situations.

The Ideal Microsurgery Fellowship: A Survey of Fellows and Fellowship Directors.

BACKGROUND: Although microsurgery fellowships have existed since the 1980s, there is no established curriculum. Microsurgery fellowships vary greatly in clinical caseload, case diversity, and training resources, and there is no consensus on the appropriate composition of a microsurgery fellowship. This study surveys fellowship directors (FD) and recent microsurgery fellows (MFs), graduates, to describe the ideal microsurgery fellowship program. METHODS: A 15-item questionnaire was sent to 38 FDs and 90 recent microsurgery fellowship graduates. This questionnaire addressed program attributes, case volumes and compositions, ideal experiences, and time allocation to different fellowship experiences. Data were analyzed using descriptive statistics, t-tests, and Chi-squared tests. RESULTS: The FD and MF surveys had a response rate of 47 and 49%, respectively. Both MF and FD agreed that exposure to microsurgical breast reconstruction is the most important characteristic of a microsurgery fellowship (p = 0.94). MF ranked replantation and supermicro/lymphatic surgery as the next most important microsurgical cases, while FD ranked the anterolateral thigh (ALT) flap and free fibula flap (p < 0.001). Both agreed that revisional surgery after microsurgical reconstruction is a very valuable fellowship experience (p = 0.679). Both agreed that 1 day of clinic a week is sufficient. CONCLUSION: Microsurgical training programs vary in quality and resources. The ideal microsurgery fellowship prioritized breast reconstruction, head and neck reconstruction, and lower extremity reconstruction. Although microsurgical technical expertise is important, a fellowship should also train in revisional surgeries and clinical decision making.

Intranasal oxytocin as a treatment for chronic pelvic pain: A randomized controlled feasibility study.

OBJECTIVE: To investigate the effect of intranasal oxytocin on chronic pelvic pain in a randomized, double-blind, within-subject crossover trial. Aims included: (1) determine intranasal oxytocin's effect on pain intensity and pain interference relative to placebo; (2) assess feasibility and acceptability. METHODS: Women with chronic pelvic pain were recruited from chronic pain and gynecology clinics between September 2017 and December 2018. Pain was recorded at pre-trial screening, and while administering intranasal oxytocin and placebo. Pain and pain-related interference were measured using the Brief Pain Inventory - Short Form. Feasibility and acceptability were measured using validated measures and interviews. RESULTS: Twenty-one women were randomized with sufficient data available from 12 to permit analyses. Relative to placebo, a 2-week course of oxytocin administration resulted in improvement in pain severity with no effect on pain-related interference. This effect was driven by four women who demonstrated a minimal clinically significant improvement in pain following intranasal oxytocin (no women met this threshold for placebo). Adherence to dosing was excellent and occurrence of adverse effects did not differ between oxytocin and placebo. CONCLUSION: Intranasal oxytocin may represent an adjuvant analgesic that could result in a minimal clinically significant improvement in pain among one in three women with chronic pelvic pain. Registration: ClinicalTrials.gov (Registration# NCT02888574).

Postprandial Glucose Spikes, an Important Contributor to Cardiovascular Disease in Diabetes?

Clinical trials investigating whether glucose lowering treatment reduces the risk of CVD in diabetes have thus far yielded mixed results. However, this doesn't rule out the possibility of hyperglycemia playing a major causal role in promoting CVD or elevating CVD risk. In fact, lowering glucose appears to promote some beneficial long-term effects, and continuous glucose monitoring devices have revealed that postprandial spikes of hyperglycemia occur frequently, and may be an important determinant of CVD risk. It is proposed that these short, intermittent bursts of hyperglycemia may have detrimental effects on several organ systems including the vasculature and the hematopoietic system collectively contributing to the state of elevated CVD risk in diabetes. In this review, we summarize the potential mechanisms through which hyperglycemic spikes may increase atherosclerosis and how new and emerging interventions may combat this.

Effects of Yoga-Based Interventions on Cancer-Associated Cognitive Decline: a Systematic Review.

PURPOSE OF REVIEW: To summarize and evaluate evidence available on the effects of yoga on cancer-associated cognitive decline (CACD). RECENT FINDINGS: A systematic review was conducted using four databases of articles published before January 1, 2020. Ten articles met the inclusion criteria (six randomized controlled trials, two single-arm studies, one non-randomized controlled trial, and one case series study). Studies were predominantly conducted with breast cancer patients using low-intensity hatha yoga programs. Of the 10 articles, five reported some positive effects on CACD, but significant biases were possible due to design shortcomings. Cohen's d effect sizes ranged from |0.03| to |0.74|. The evidence to date is insufficient to suggest that yoga is beneficial for attenuating CACD. More rigorous trials controlling for non-specific factors are warranted. The field would also benefit from examining self-delivered modes of yoga for treating CACD in various cancer populations to enhance practice sustainability and generalizability.

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

RATIONALE: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. OBJECTIVE: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. METHODS AND RESULTS: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. CONCLUSIONS: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

S100 family proteins in inflammation and beyond.

The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases. Strategies aimed at targeting S100-mediated signaling pathways hold a great potential in developing novel therapeutics for multiple diseases. In this chapter, we aim to summarize the current knowledge about the role of S100 family proteins in health and disease with a major focus on their role in inflammatory conditions.

Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16- Monocytes.

Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14+CD16- monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14+CD16- monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14+CD16- monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.

Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis.

Atherosclerotic cardiovascular disease (CVD) is a lipid-driven chronic inflammatory disease, in which macrophages are responsible for taking up these lipids and driving disease progression. Over the years, we and others have uncovered key pathways that regulate macrophage number/function and identified how metabolic disorders such as diabetes and obesity, which are common risk factors for CVD, exacerbate these pathways. This ultimately accelerates the progression of atherosclerosis and hinders atherosclerotic regression. In this review, we discuss the different types of macrophages, from monocyte-derived macrophages, local macrophage proliferation, to macrophage-like vascular smooth muscle cells, that contribute to atherosclerosis as well as myeloid-derived suppressor cells that may have anti-atherogenic effects. We will also discuss how diabetes and obesity influence plaque macrophage accumulation and monocyte production (myelopoiesis) to promote atherogenesis as well as an exciting therapeutic target, S100A8/A9, which mediates myelopoiesis in response to both diabetes and obesity, shown to be effective in reducing atherosclerosis in pre-clinical models of diabetes.

Fat for fuel: lipid metabolism in haematopoiesis.

The importance of metabolic regulation in the immune system has launched back into the limelight in recent years. Various metabolic pathways have been examined in the context of their contribution to maintaining immune cell homeostasis and function. Moreover, this regulation is also important in the immune cell precursors, where metabolism controls their maintenance and cell fate. This review will discuss lipid metabolism in the context of haematopoiesis, that is blood cell development. We specifically focus on nonoxidative lipid metabolism which encapsulates the synthesis and degradation of the major lipid classes such as phospholipids, sphingolipids and sterols. We will also discuss how these metabolic processes are affected by haematological malignancies such as leukaemia and lymphoma, which are known to have altered metabolism, and how these different pathways contribute to the pathology.